Simvastatin Augmentation for Patients With Early-Phase Schizophrenia-Spectrum Disorders: A Double-Blind, Randomized Placebo-Controlled Trial

Abstract

Schizophrenia-spectrum disorders (SSD) are associated with increased inflammatory markers, both in brain and periphery. Augmentation with drugs that lower this pro-inflammatory status may improve clinical presentation. Simvastatin crosses the blood-brain barrier, has anti- inflammatory and neuroprotective effects and reduces metabolic syndrome. In this study, we investigated if 12 months of simvastatin augmentation can improve symptoms and cognition in patients with early SSD. This double-blind placebo-controlled trial included 127 SSD patients across the Netherlands, <3 years after their diagnosis. From these, 119 were randomly assigned 1:1 to simvastatin 40 mg (n = 61) or placebo (n = 58), stratified for sex and study site. Primary outcomes were symptom severity and cognition after 12 months of treatment. Depression, symptom subscores, general functioning, metabolic syndrome, movement disorders, and safety were secondary outcomes. Intention to treat analyses were performed using linear mixed models and ANCOVA. No main effect of simvastatin treatment was found on total symptom severity after 12 months of treatment as compared to placebo (X2(1) = 0.01, P = .90). Group differences varied over time (treatment*time X2(4) = 11.2; P = .025), with significantly lower symptom severity in the simvastatin group after 6 months (mean difference = −4.8; P = .021; 95% CI: −8.8 to −0.7) and at 24 months follow-up (mean difference = −4.7; P = .040; 95% CI: −9.3 to −0.2). No main treatment effect was found for cognition (F(1,0.1) = 0.37, P = .55) or secondary outcomes. SAEs occurred more frequently with placebo (19%) than with simvastatin (6.6%). This negative finding corroborates other large scale studies on aspirin, minocycline, and celecoxib that could not replicate positive findings of smaller studies, and suggests that anti-inflammatory augmentation does not improve the clinical presentation of SSD.

Anti-inflammatory medications for the treatment of mental disorders: A scoping review

“…A trial of Pravastatin augmentation of TAU did not show any significant benefit in outcomes except for a significant decrease in the PANSS positive symptoms score at 6 weeks; however, this was not seen at the 12-week study endpoint ( Vincenzi et al, 2014 ). Simvastatin augmentation of TAU resulted in lower total PANSS scores in the Simvastatin group at 6 and 24 months; however, there were no significant difference at pre-defined end point of 12 months ( Sommer et al, 2021 ). A trial of Pioglitazone as an adjunct to Risperidone showed a significant reduction in negative subscale and total PANSS at 8 weeks in the Pioglitazone group compared to placebo ( Iranpour et al, 2016 ).…”

Diagnostic model development for schizophrenia based on peripheral blood mononuclear cell subtype-specific expression of metabolic markers

“…Samples and data analysed in the present study were collected as part of the clinical trial of simvastatin supplementation in schizophrenia (ClinicalTrials.gov identifier: NCT01999309 [ 17 , 18 ]). The study population consisted of 119 participants between 18 and 50 years old diagnosed with schizophrenia spectrum disorder using the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) [ 19 ] guidelines.…”

Prenatal and Childhood Immuno-Metabolic Risk Factors for Adult Depression and Psychosis

“…65,94,[187][188][189][190][191] In schizophrenia and psychosis, evidence is also restricted; a few, relatively small RCTs have tested anti-inflammatory drugs, including the tetracyclic minocycline, the statin simvastatin, nonsteroidal anti-inflammatory drugs such as aspirin or celecoxib, and the anti-IL-6R monoclonal antibody tocilizumab, as adjuncts to standard antipsychotic medication. [192][193][194][195][196][197][198][199][200][201] As summarized in a recent meta-analysis, these RCTs reported promising results for some drugs, particularly regarding negative symptoms of schizophrenia that are usually difficult to treat. [192][193][194][195][196][197] There were also notable negative findings, however, warranting replication in larger RCTs that should selectively recruit patients with early psychosis and high baseline levels of inflammation.…”

“…[192][193][194][195][196][197] There were also notable negative findings, however, warranting replication in larger RCTs that should selectively recruit patients with early psychosis and high baseline levels of inflammation. [198][199][200][201][202] Overall, the evidence from RCTs of anti-inflammatory treatments for depression and psychosis makes apparent that these treatments are unlikely to provide a uniform treatment strategy for all patients. This is not a surprise, as immunometabolic alterations are not universally present in all cases of depression or psychosis.…”